Hidden Allosteric Site on Cereblon Modulates Drug Efficacy

These results were observed under controlled laboratory conditions, so real-world performance may differ.

Scientists have identified a functional 'control switch' on the protein **Cereblon**, enabling precise tuning of how cancer drugs degrade their targets. This discovery addresses a limitation in current thalidomide-based therapies: the reliance on a single binding site. By engaging a newly found pocket, researchers can now modify the behaviour of established medicines, potentially increasing their potency against haematologic neoplasias.

The Limits of Orthosteric Cereblon Binding

Therapeutic efficacy in targeted protein degradation currently depends on thalidomide derivatives. These drugs target the orthosteric site of Cereblon (CRBN). They function as molecular glues, recruiting specific proteins—termed neosubstrates—for elimination. While this primary pocket has undergone intense investigation, alternate binding sites remained unknown. Relying on one site restricts the ability to differentiate between disease-causing proteins and healthy tissue. The field required a new method to manipulate the protein's activity without displacing the primary drug.

Uncovering a Cryptic Allosteric Site

Researchers report the identification of an evolutionarily conserved, cryptic pocket on CRBN. This site is distinct from the standard drug-binding region. The team characterised a small molecule, SB-405483, which binds specifically to this allosteric site. SB-405483 does not compete with standard drugs. Instead, it works cooperatively. When this molecule attaches to the allosteric site, it enhances the binding ability of orthosteric ligands. This creates a dual-occupancy system where the regulator and the drug work in tandem. A survey of over 100 orthosteric ligands demonstrated that this combination alters degradation profiles significantly. In some cases, the destruction of target proteins was amplified; in others, it was inhibited. This suggests a tunable system where efficacy is dialled up or down based on the specific chemical combination.

Mechanism: Shifting Conformational States

Structural investigations provide the physical basis for this modulation. CRBN exists in various shapes or conformations. Laboratory data indicates that SB-405483 shifts the conformational distribution of the protein. It moves CRBN from an 'open' state to a novel 'intermediate' state (CRBNint) and increases the population of the 'closed' state (CRBNclosed). Proteins are dynamic, not static. By stabilising these specific shapes, the allosteric ligand changes the surface geometry of CRBN. This geometric shift dictates which neosubstrates can be recruited and destroyed. The molecule effectively reshapes the clamp, altering its grip on target proteins.

Implications for Therapeutic Selectivity

The discovery of this site offers a new strategic avenue for drug development. Current orthosteric inhibitors are effective but limited by a lack of alternative binding options. The ability to modulate CRBN allosterically implies that developers can fine-tune the functional effects of established medicines. By adding an allosteric binder, a drug's selectivity for a specific cancer target could be improved. Furthermore, this mechanism suggests that CRBN is more plastic than previously modelled. Future therapeutics might utilise dual-targeting strategies—occupying both the orthosteric and allosteric sites—to expand the capabilities of current treatments. This represents a move towards high-precision protein degradation.